Paralytic shellfish poisoning (PSP) results from a mixture of phycotoxins that bind reversibly to a receptor site on the voltage-gated sodium channel found in excitable cells. The primary clinical symptom is an acute paralytic illness. Phycotoxins or algal toxins are produced by microscopic planktonic algae. These toxins accumulate on filter feeders such as bivalves. Consumption of phycotoxin-contaminated shellfish results in six diseases in humans: PSP, Diarrhetic shellfish poisoning (DSP), amnesic shellfish poisoning (ASP), neurotoxic shellfish poisoning (NSP), ciguatera poisoning (CP) and cyanobacterial poisoning (CNP).
The phycotoxins that produce PSP have a common structure of 3,4,6-trialquil tetrahidropurine. Twenty-six naturally occurring phycotoxins have been described. These phycotoxins are non-protein, low molecular weight compounds of between 289 and 450 daltons. The gonyautoxins (GTX's) are the most abundant of these phycotoxins found in shellfish extract occurring over 80% of the total toxin content.
The high toxicity of these phycotoxins is due to reversible binding to a receptor site on the voltage-gated sodium channel on excitable cells, thus blocking the influx of sodium ions and preventing nerve and muscle cells from producing action potentials, thereby blocking neuronal transmission and causing death in mammals via respiratory arrest and cardiovascular shock. Application of small amounts of these phycotoxins can produce a flaccid paralysis of striated muscle for periods that are dose dependent.
The presence of wrinkles in the neck and face of people are seen as negative aesthetic effects by social groups. These marks reflect facial aging and increase the subjective awareness of the age of people. Since the beginning of civilization, natural or synthetic chemical compounds have been used and procedures have been developed (i.e. plastic surgery) to alleviate this problem. For example, plastic surgeons and cosmetic centers have been experimenting with, and using, Botulin A toxin as a pharmaceutical preparation that produces facial rejuvenation by removing face wrinkles. Botulin A toxin is a neurotoxin that acts by chemodenervation, or blocking the presynaptic release of the neurotransmitter acetylcholine in the neuromuscular plate, thus interfering with neuromuscular transmission, paralyzing the muscle and preventing its contraction for a period of up to 4 months. Applied locally in the face of people, its effect is a facial rejuvenation that appears within 5-7 days after the toxin is applied. The facial rejuvenation from a dose of Botulin A toxin typically has a duration of approximately 4 months. Botulin A toxin has been used for the treatment of diseases associated with muscular spasm, focal dystonia, sphincter relaxation (achalasia and anal fissure), hyperhydrosis and urinary bladder relaxation.
While Botulin A toxin is effective as a facial rejuvenate, it is an enzyme that is inherently unstable. This instability makes its use and handling problematic. In fact, it requires freezing before use, and it must be used within four hours of opening the container. Because it is an enzyme, Botulin A toxin also generates antibodies that prevent its use in consecutive injections and it can induce an allergic response. In addition, its results are delayed 5-7 days, which is undesirable for patients wanting an immediate result. Another problem with Botulin A toxin is that it leaves a marbled look when used as a facial rejuvenate. Accordingly, a need exists for a facial rejuvenate that is stable, fast-acting, provides a more natural look, and which is not an enzyme.
The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences—e.g., gastrointestinal irritation and the like—are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum (the outer layer of the epidermis), which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low without the use of some means to enhance the permeability of the skin.
In order to increase the rate at which a drug penetrates through the skin, then, various approaches have been followed, many of which involve the use of either a chemical penetration enhancer or a physical penetration enhancer. Physical enhancement of skin permeation includes, for example, electrophoretic techniques such as iontophoresis. The use of ultrasound (or “phonophoresis”) as a physical penetration enhancer has also been researched. Chemical penetration enhancers are compounds that are administered along with the drug (or in some cases the skin may be pretreated with a chemical enhancer) in order to increase the permeability of the stratum corneum, and thereby provide for enhanced penetration of the drug through the skin. Ideally, such chemical penetration enhancers (or “permeation enhancers,” as the compounds are referred to herein) are compounds that are innocuous and serve merely to facilitate diffusion of the drug through the stratum corneum.
Nevertheless, the number of drugs that can be safely and effectively administered through the skin, without concomitant problems such as irritation and sensitization, remains limited.
There are a number of approaches to the delivery of drugs and other compounds transdermally. For example, in U.S. Pat. No. 4,818,541, transdermal systems are disclosed for delivering phenylpropanolamine to the skin. In the aforementioned patent, however, it is noted that the skin flux of (±)-phenylpropanolamine (i.e., a mixture of (−)-norephedrine and (+)-norephedrine) is only 16 microg/cm2/hr, although the skin flux of individual enantiomers was found to be higher. Furthermore, the method of the '541 patent requires neutralization of phenylpropanolamine hydrochloride (i.e., conversion to the free base), the commercially available form of the drug, before incorporation into a transdermal drug delivery system.
Similarly, U.S. Pat. No. 6,299,902 describes an improved transdermal absorption and efficacy for a local anesthetic. The transdermal preparation contains at least one local anesthetic agent and at least two melting point depressing agents. Also described is a two-phase liquid composition that contains aqueous and oil phases, the oil phase having a relatively high concentration of a local anesthetic agent to enhance transdermal absorption and efficacy when incorporated into an anesthetic preparation. A preferred anesthetic preparation includes lidocaine or tetracaine, thymol or menthol, and ethyl alcohol or isopropyl alcohol.
Although many chemical permeation enhancers are known, there is an ongoing need for specific transdermal pharmaceutical formulations which include chemical permeation enhancers that are highly effective in increasing the rate at which a drug permeates the skin, and do not result in skin damage, irritation, sensitization, or the like.